Sunday, December 9, 2012

That genes within the major histocompatibility complex (MHC, human HLA) influence
susceptibility to rheumatoid arthritis (RA) has been known for over 40 years, even before HLA nomenclature was well established (e.g., Dick et al. 1975). However, the few “classical” HLA genes constitute only a small fraction of the hundreds genes within the MHC, which include the inflammatory cytokine tumor necrosis factor (TNF), a key player in RA. Which genes are responsible for the association?

First they tested their ability to “impute” HLA alleles from their SNP data using a
reference panel of 2,767 individuals. Conclusion, not bad: 98% accuracy for “two digit” mapping and >80% for 4 digit (allele). Then they found the most significant nucleotide (p<10^-526!) is part of a codon for amino acid 11 of the HLA-DR beta 1,
and thus not part of the “shared epitope” (a 5-amino acid sequence and antibody epitope linked to RA [review]). A valine at this position confers a 3.8-fold higher risk whereas a (polar) serine is protective (the converse of risk). Comparing cases and controls shows a clear difference (shown here, from fig 3). Adding amino acids at positions 71 and 74 improved significance slightly, and alleles with these amino acids were independently shown to confer risk.

The authors conclude “These results are consistent with a disease model in which
classical HLA genes and proteins are the dominant factors in rheumatoid arthritis pathogenesis, with only a minor contribution from non-HLA loci in the MHC”. It seems that someone might also explore whether these variants bind CCP better!

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